Prof. Joshua Lederberg, former President of Rockefeller University, once told me while he
was Chairman of the Genetics Department at Stanford Medical School, "Pushing the envelope in
science is more about knowing what questions to ask than it is about toiling in
the lab. Once you have what you believe to be a good hypothesis, you've got to go back to
the lab and get the needle to point slightly to the right or slightly to the left before
you invest a lot more effort."

Assignment No. 1: Generate and submit your own list of the "Top Ten
Unsolved Problems in Aging Research." This assignment may be submitted by E-mail at any time
(scoles@grg.org), but is formally due on February 10, 1997 at our next meeting. The criteria for
this problem list includes well-defined Ph.D.-Thesis Topics that can be accomplished by a
respectable graduate student in biology within a 1-2 year period. Another criterion is that a
solution to the problem will advance our agenda (as defined in our Charter, posted on the web).
The list will then be edited, compiled, and reviewed over the coming months to see if we can
establish a consensus, after which we will post it in a conspicuous place on our LA-GRG home
page for external comment.

Other lists can be found in Strehler's "100 Unsolved Problems" [pp. 375-388, Bernard
L. Strehler, Time, Cells, and Aging (2nd Edition; Academic Press, New York;
1977)] or in Finch's Agenda [pp. 4, 646-652, Caleb E. Finch, Longevity, Senescence, and the
Genome (University of Chicago Press, Chicago, Illinois; 1990)]. My own list follows, but I
suggest you generate your own list before looking at it, lest you be overly biased before you get
started.

1. Centenarians: Demographics of Human Senescence... Johnny
Carson regularly interviewed centenarians on the Tonight Show with the aim of amusing
his audience with their curious, self-serving answers. When George Burns was asked at the age of
100 to what he owed his great longevity, he answered "Hard work and smoking at least one if not
several cigars a day. By the way, when my doctors advised me to stop smoking, I always ignored
them. Anyway it really doesn't matter; they're all dead!"

The odds of reaching 100 years of age in most industrialized countries is now about 1
in 20,000 or 0.005 percent. In the U.S. there are on the order of 50-70K such individuals, many in
nursing homes. Census numbers are soft on many of these alleged centenarians due to poor
documentation. Birth certificates before the year 1900 were rarely recorded with precision, and
social security numbers didn't exist at that time. For example, Shigechiyo Izumi of Japan was
included in the Guinness Book of World Records as the longest-lived man at 120 years,
but most experts now regard his death as "only" 105. The runner up was Pierre Joubert of
Quebec, Canada at 113, but this too has now been debunked. The Shangri-La tales of
superlongevous tribes in Vilcabamba, Peru and other places was discredited in the 1970s. The
biblical patriarchs like Methuselah probably slipped a decimal point at 969 years.

What is special about centenarians as a group, if anything, that explains their
longevity? Can we learn anything from identical-twin studies of centenarian twins reared-apart
that will distinguish genetic factors from environmental factors? Are there enough of such
persons to even do a study? The French are conducting such a study on their own population. By
the way, the world's oldest documented person was the French woman, Jeanne Calment, who
passed away at 122 years of age. The oldest living male is now presumed to be Mr. Herbert
Young of Harlem, New York at age 112. The second oldest living male is now 111 years.
[Source: French demographer, Jean-Marie Robine] Can we set up a database to gather
information as to their life styles, diet/fasting, alcohol intake, athletic ability, IQs, occupation(s),
marriage(s), ages at death of all first-degree relatives and causes of death? Has the NIA ever
proposed a study of Centenarian blood chemistry or anti-oxidant profiles?

3. Caloric Restriction: What is the mechanism of life extension by dietary
restriction? Is it related to body-temperature thermostats or basal metabolic rates? Is it related to
a reduction in chaperon proteins (Prof. Spindler, UC Riverside) that leads to significant
non-biologically active protein structural synthesis that triggers apoptosis and then subsequently
increased cellular replication, which is the only thing that is really rejuvenating?

4. Telomere Shortening: What will telomerase do for longevity? Can the
Hayflick Limit be made to exceed 50 +/- 10? [Revised Answer = Yes.] What about the Hayflick
limit for paramecia, something over 200 mitotic divisions? However, post sexual conjugation, the
telomeres are reset in some fashion. How?

Is telomere shortening directly proportional to the relentless linear decline with age in
epithelial tissue repair efficiency in response to injury?

5. Progeria: What are the age-accelerating mechanisms of Downs, Progeria
(Hutchinson-Gilford Syndrome), or Werner's Syndrome (helicase mutation)? Are these true
metaphors for aging or are they merely cartoons of normal aging?

6. Mitochondria: What switches on the synthesis of new mitochondria and/or the
scavenging of "burnt out" mitochondria (conversion to lipofuscin)? Do mitochondria go
through a process of mitosis in response to signals from the nucleus about their average density in
the cytoplasm? What dictates hypomitochondriosis? What rejuvenates mitochondria in
eggs post fertilization (with a few exceptions, spermatic mitochondria never enter the egg after
head penetration, so mtDNA is almost always feminine, the "original Eve")? Can fetal
mitochondria be transplanted into old cells and function? Is the potential lifespan of all
mitochondria and their progeny in dividing somatic cells no greater than 130 years, as
extrapolated from semilog plots?

Click here to see what the pseudo-three-dimensional
structure of mitrochondria looks like and a legend providing more detailed information about the
images.

7. Human Growth Hormone: Can we develop oral secretagogues for all
anterior pituitary hormones? Merck has given up a promising line of research for what appear to
be marketing reasons.

8. Free Radicals: What do free radicals (tanning) and glycosylating agents
(caramelization) have in common in promoting aging? And can they be reversed with antioxidants
and/or solvents?

Click here to see a cartoon of how nanotechnology might
be used to repair blood vessels.

Click on Zyvex, Inc. to find out how a
Richardson, TX company plans to construct nanotechnology assemblers.

10. Compression of Morbidity Hypothesis: Will there be a "compression of
morbidity" as we increasingly rectangularize the human longevity/mortality curves (as predicted
by the James Fries of Stanford University)? In support of this notion, a recent study reported
in the March 18, 1996 issue of PNAS suggests that Americans are now suffering
fewer disabilities in their senior years. Other relevant papers have been reviewed in
JAAM, Vol 1, No. 3.

If you have strong opinions about or are interested in working on one of these questions as a
research topic, please link to Stanley R. Primmer's personal
solution to Assignment No. 1 where you will find detailed discussions and provocative
speculation at the "cutting edge" of gerontology research today. Any other solutions to
Assignment No. 1 will be welcome. We challenge you to send your solution by E-mail to scoles@grg.org. A team of ten professionals from the
LA-GRG will review and critique all entries, the best of which will be posted along with Stan
Primmer's contribution on this site.